Off-Label Use of Alzheimer’s Drugs

For those who have lost the attachment to a loved one’s
mind suffering from Alzheimer’s disease, there is hardly anything more
devastating. This spouse, mother, father, sister, brother, or friend
that you have known and loved slowly but distinctly loses touch with
reality, and the day of reckoning comes when you see this person and
they do not know who you are anymore. And the “good days” when the
illness retreats and lets memories rise, if only for a while, never seem
to make up for the “bad days” when you are just another figure in this
person’s life.

The hardship of this demoralizing malady is something that
almost everyone with this experience wants to rile against it with all
the fervor and frustration of Dylan Thomas’s famous poem written while
his own father was dying: “Do not go gentle into that good night…Rage,
rage against the dying of the light.”1

The statistics are not very encouraging. Today about 4.5
million Americans have some form of advanced neurodegeneration, and
there are estimates that by 2050 the disease state will affect as many
as 14 million people. Worse, Alzheimer’s disease is said to affect 1 out
of 4 people over age 75 years, 1 out of 3 people over age 80, and
nearly half of those over age 85. The Alzheimer’s Drug Discovery
Foundation estimates that this disorder costs the United States over
$183 million annually, just slightly behind the most expensive
diseases—cancer and cardiac complications.2

FDA-Approved Treatments

Drugs that have been approved by the FDA have been divided
into categories that refer to the degree of Alzheimer’s disease:
mild-to-moderate or moderate-to-severe. For mild-to-moderate Alzheimer’s
disease, cholinesterase inhibitors such as donepezil (Aricept; also
approved for moderate-to-severe disease), galantamine (Razadyne), and
rivastigmine (Exelon) are prescribed. According to the National
Institute on Aging, “these drugs may help delay or prevent symptoms from
becoming worse for a limited time and may help control some behavioral
symptoms.”3

The N-methyl-
D-aspartate
(NMDA) antagonist memantine (Namenda) is used to treat
moderate-to-severe Alzheimer’s disease. Its main effect is to delay
progression of symptoms, which allows patients to maintain certain daily
functions (e.g., ability to use the bathroom independently) for a
little longer than they would without the drug. Memantine regulates
glutamate, an important brain chemical that in excessive amounts may
lead to brain cell death.NMDA antagonists and cholinesterase
inhibitors can be used in combination because they have very different
mechanisms of action (TABLE 1).4

The Search for New Treatments

It should come as no surprise to anyone that drug
companies and researchers are urgently seeking compounds to fight this
awful illness. It seems that grant money to study drugs that will slow
the onset of the disease and alleviate some of its worst symptoms
abound.5 Take note that the majority of the ongoing and
developing research is not targeting a cure. At this point in time,
curing the disease does not seem feasible.6

This little detail does not seem to deter Americans clamoring for hope and relief.7 The journal Science
recently published research data showing that a drug used to treat a
particular form of skin cancer (bexarotene [Targretin] for cutaneous
T-cell lymphoma), improved brain function in mice bred with a form of
Alzheimer’s disease.8-10 Improvements in social skills and the sense of smell and a decrease in brain amyloid-beta protein fragments were notable.

The drug has not been tested in humans at this time.
Nonetheless, patients, relatives, and friends of patients have deluged
physicians across the country begging that bexarotene be prescribed for
Alzheimer’s patients. It appears that in just 1 or 2 days following
publication of these results, in a scientific journal not necessarily
identified as widely read by the general public, physicians and advocacy
groups started getting a flurry of calls from patients seeking to use
the drug off-label. “The Alzheimer’s community is very desperate for
anything that shows any sign of hope or promise,” said Eric Hall, chief
executive of the Alzheimer’s Foundation of America, a New York-based
advocacy organization that started to field calls from consumers as soon
as the paper was published.11

Sam Gandy, MD, PhD, a neurology professor at the Mount
Sinai School of Medicine and director of its Alzheimer’s Disease
Research Center, was not surprised by the flood of inquiries for the use
of bexarotene in his Alzheimer’s patients. He stated, “they also often
ask for off-label use of another treatment on the market, intravenous
immunoglobulin, which costs about $50,000 a year and is given in
time-consuming infusions. To patients and families who are this
motivated, the idea of an off-label pill is not a major leap. The cost
would be $1,200 or more a month and unlikely to be covered by
insurance.”12

Commentary

Depending on one’s perspective, the lack of any human
research unfortunately means most physicians will not prescribe the drug
for their suffering patients. While there may be some room for moral
arguments favoring administration of the drug to individuals inflicted
with Alzheimer’s disease, from a legal standpoint, there is no
justification for doing so right now.

This situation needs to serve as a reminder to pharmacists
that off-label prescribing, while usually legal, can be fraught with
many uncertainties including legal liabilities. The old saw,
“Prescribers may prescribe and pharmacists may dispense an FDA-approved
drug for an indication not approved by the FDA so long as there is a
body of evidence, usually in the form of peer-reviewed literature that
it is an acceptable practice within the bounds of reasonable standards
of health care to do so as long as the unapproved use does not
constitute experimentation” holds true.13,14 While
pharmacists may not necessarily know exactly what a patient is using any
particular drug for, there is always the “reasonable man” test for
negligent behavior.15 In this context, the question would be
whether a reasonable pharmacist in the same or similar circumstances
knows or should know that the drug is being used off-label or
experimentally.

While there are, in fact, drugs now being used for
off-label purposes to treat Alzheimer’s disease, anyone prescribing
bexarotene for an Alzheimer’s patient is taking a mighty big risk. The
same would hold true for pharmacists if they know this drug is being
prescribed for Alzheimer’s disease and not for the very specific type of
skin cancer for which it is approved. As badly as Alzheimer’s
advocates, patients, and loved ones are begging for a chance (an
“anything with promise is better than nothing” mentality) to try this
drug, it does not, at this moment in time, meet the test set forth
above.16 There is no body of evidence in any peer-reviewed
journals suggesting use of this drug for Alzheimer’s is reasonable with
the state of knowledge we have before us today. Such use would no doubt
come under the heading of unacceptable human experimentation, opening
prescribers and pharmacists to potential criminal and civil charges.

The manufacturer of bexarotene, Eisai Co., based in Japan,
is being a bit vague in its public statements about this potential
off-label use of its product. Instead of coming right out and saying
that the drug should not be used in humans until further research is
performed, its spokesperson was quoted as saying, “It is our policy to
not comment on off-label uses of our products. Physicians are able to
prescribe products as they see medically necessary.” The company also
disavowed any knowledge of the research study published in Science.17

That is a great way for a company to have its cake and eat
it too. Companies can say that they do not have any control of how
their products are used once they leave their factories, but they will
be happy to take the profits from off-label uses if such an occurrence
happens. While this may well be an accurate point of view at some time
down the road when human-use evidence is collected, from an ethical
perspective, the company should be saying this drug has been approved in
the U.S. for a very narrow and specific use and should not be used for
other purposes at this time. Perhaps that time could come in a
relatively short period if clinical trials were opened under the
auspices of an FDA Investigational New Drug Application (INDA) with the
approval of the Institutional Research Board (IRB) where the research
might be conducted.

Depending on which data is used or the type of diseases
involved, the rate of off-label prescribing of prescription drugs in the
U.S. ranges from a conservative 20% to as high as 75%.18,19
In the majority of cases, using drugs for purposes not approved by the
FDA will not expose pharmacists to extraordinary risks of legal
liability. However, when a report like the one discussed here is
released and throngs of patients, caregivers, and even physicians start
demanding a prescription drug under these circumstances, pharmacists
should be very wary of complying. Perhaps the line between
experimentation and acceptable off-label use is gray, but a reasonable
pharmacist staying abreast of the current literature should know the
difference.

U.S. Pharmacist is a monthly journal dedicated to providing the nation's pharmacists with up-to-date,
authoritative, peer-reviewed clinical articles relevant to contemporary pharmacy practice in a variety of settings,
including community pharmacy, hospitals, managed care systems, ambulatory care clinics, home care organizations,
long-term care facilities, industry and academia. The publication is also useful to pharmacy technicians, students,
other health professionals and individuals interested in health management. Pharmacists licensed in the U.S. can earn
Continuing Education credits through Postgraduate Healthcare Education, LLC, accredited by the Accreditation Council for Pharmacy Education (ACPE)
as a provider of continuing pharmacy education.